PROJECT SUMMARY/ABSTRACT The rising prevalence of severe obesity in early childhood, especially in underrepresented minorities, is a challenge to the cardio-metabolic health of our youth. Although largely attributed to the environment, heredity plays a significant role in determining adiposity. The influence of these genetic factors is largely undefined in children from underrepresented minorities where the prevalence is the highest. This study seeks to identify the rare genetic variants contributing to severe obesity in a large cohort of children with severe early onset obesity from mixed ethnic groups. The primary goal is to explain the biology of extreme obesity by understanding the effects of genetic variants on physiological attributes leading to extreme obesity. We hypothesize that the burden of genetic variants related to obesity will be higher in children with severe early onset of obesity, The sample of subjects is selected from children with severe obesity (BMI > 120% of the 95th percentile, equivalent to Class II obesity or higher), documented at an age less than 6 years. We have established a large multi-institutional collaborative cohort including a prospective family study of children attending the clinics at Boston Children?s Hospital that serve large populations of underrepresented minorities, a cohort at Children?s Hospital of Philadelphia using data extraction from the electronic health records and samples from the biorepository and a research cohort from the Columbia University Medical Center. For the prospective family study, children with severe obesity and their first-degree relatives are invited to participate in the study. In the collaborative cohort, we will perform whole exome sequencing in children with extremes of obesity, most rapid trajectory of growth of body mass index and those with family structure favorable for mendelian pattern of inheritance. We will perform targeted sequencing of approximately 80 genes including those causing syndromic and non-syndromic forms of obesity, and those prioritized in the whole exome study in all other samples. We will develop an integrated genetic risk score based on the common and identified rare genetic variants, and correlate it with the longitudinal BMI trajectories and cardio-metabolic consequences extracted from the electronic health records. Additionally, we will perform metabolic phenotyping including energy intake and expenditure, body composition and hormonal response to a standard meal in a subgroup from the extreme tails of the genetic risk scores to understand the differences in physiology leading to severe obesity. Individuals of different genetic ancestries can have different patterns of genetic variation. It is possible that studying multiple ethnicities may identify new genes. Children with rare variants of large effect, or varying genetic risk scores could help describe differences in physiology uncovering therapeutic targets, or a response to treatment that could eventually influence clinical care. Finally, our study cohort of underrepresented minorities will provide a unique replication/extension cohort for other large-scale genetic studies in children with severe obesity.